title: Activin A induction of erythroid differentiation sensitizes K562 chronic myeloid leukemia cells to a subtoxic concentration of imatinib.
abstract: Chronic myeloid leukemia (CML) is a hematopoietic stem/progenitor cell disorder in which Bcr-Abl oncoprotein inhibits cell differentiation. Differentiation induction is considered an alternative strategy for treating CML. Activin A, a member of the transforming growth factor-β superfamily, induces erythroid differentiation of CML cells through the p38 MAPK pathway. In this study, treatment of the K562 CML stem/progenitor cell line with activin A followed by a subtoxic concentration of the Bcr-Abl inhibitor imatinib strongly induced growth inhibition and apoptosis compared with simultaneous treatment with activin A and imatinib. Imatinib-induced growth inhibition and apoptosis following activin A pretreatment were dose- and time-dependent. Imatinib-induced growth inhibition and apoptosis were also dependent on the pretreatment dose of activin A. More than 90% of the activin A-induced increases in glycophorin A-positive cells were sensitive to imatinib. However, only some of original glycophorin A-positive cells in the activin A treatment group were sensitive to imatinib. Sequential treatment with activin A and imatinib decreased Bcr-Abl, procaspase-3, Mcl-1, and Bcl-xL and also induced cleavage of procaspase-3/poly(ADP-ribose)polymerase. The reduction of erythroid differentiation in p38 MAPK dominant-negative mutants or by short hairpin RNA knockdown of p38 MAPK decreased the growth inhibition and apoptosis mediated by sequential treatment with activin A and imatinib. Furthermore, the same inhibition level of multidrug resistance 1 expression was observed in cells treated with activin A alone, treated sequentially with activin A and imatinib, or treated simultaneously with activin A and imatinib. The p38 MAPK inhibitor SB-203580 can restore activin A-inhibited multidrug resistance 1 expression. Taken together, our results suggest that a subtoxic concentration of imatinib could exhibit strong cytotoxicity against erythroid-differentiated K562 CML cells.
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan;
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Huang
authors.forename: Wei-Hwa
authors.initials: WH
authors.lastname: Lee
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Tsai
authors.forename: Huei-Mei
authors.initials: HM
authors.lastname: Huang
mesh_terms: D028341:Activins / Q000096:biosynthesis* / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000633:toxicity*; D001549:Benzamides / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism; D010879:Piperazines / Q000633:toxicity*; D011743:Pyrimidines / Q000633:toxicity*; D011994:Recombinant Proteins / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D011994:Recombinant Proteins; C422405:activin A; D028341:Activins; D000068877:Imatinib Mesylate
keywords: K562 chronic myeloid leukemia cells; activin A; erythroid differentiation; imatinib; p38 MAPK